PROJECT SUMMARY Alzheimer?s disease (?AD?) is a progressive late-onset neurodegenerative disorder which manifests in memory loss and cognitive decline. AD involves the pathological accumulation of A?-enriched plaques and neurofibrillary tangles comprising phosphorylated tau in the human brain. Although neurotoxic A? oligomers are thought to contribute to neurological decline, mechanisms underlying A? clearance and A?-induced neuroinflammation invariably linked to AD onset remain elusive. In addition to familial AD mutations in APP and PS1, genome-wide association studies (GWAS) in AD have uncovered genes such as CD33, CR1, MS4A, ABCA7, EPHA1 and TREM2 enriched in microglia and myeloid cell types, suggesting that AD pathogenesis may be modulated by microglial activation and function. The microglial transmembrane receptor, TREM2 (Triggering Receptor Expressed on Myeloid cells 2) may be of particular interest as R47H ectodomain mutations have potent effects in increasing odds for triggering AD onset. Given that AD is invariably associated with a neuroinflammatory etiology, it seems likely that TREM2-related microglial function may modulate neurodegenerative AD onset. Although ligands for TREM2 such as ApoE have been previously identified, a definitive mechanism for TREM2 in AD has not been established. Here, we provide evidence that TREM2 directly binds A? oligomers with nanomolar affinity and R47H mutations attenuate TREM2/A? interaction. TREM2 deletion impairs A? turnover in primary microglia, and abrogates A? clearance in vivo. A? also triggers changes in microglial membrane potential which is impaired with TREM2 deletion. Moreover, TREM2 deletion attenuates A?-induced microglial morphogenic changes associated with activation, and inhibits A?-mediated induction of proinflammatory cytokine expression. Together, these results indicate that TREM2 may have opposing neuroprotective roles in mediating microglial A? clearance and turnover, while concurrently transducing potentially neurotoxic A?-induced inflammatory signals. To further define a role for TREM2 in A? clearance and A?-mediated microglial activation/cytokine expression, we plan to exploit use of TREM2 R47H knock-in and TREM2 WT and R47H overexpression mouse models currently housed in our laboratory to determine whether impaired TREM2/A? interactions can impair microglial response in the presence of A?. We will also characterize the role of the obligate TREM2 adaptor DAP12 in A? uptake/clearance and A?-mediated microglial activation/cytokine induction. These results will provide mechanistic insight into how TREM2/A? interaction can affect microglia-dependent A? uptake and turnover, and A?-induced microglial activation and inflammation. Given that ApoE is known to bind A? as well as TREM2, we will also determine whether microglial A? response above differs from response derived from A?/ApoE complexes. This provides essential groundwork in future strategies to optimize neuroprotective TREM2 A? clearance while limiting A?-induced microglial inflammation.